Abstract Text: Selective serotonin reuptake inhibitors (SSRIs) have been a focus of research in development of medication for cocaine dependence, in part because preclinical studies have shown that manipulation of the serotonin (5-HT) system affects cocaine self administration and drug reinstatement. Some of the strongest human data supporting examination of one particular SSRI for cocaine dependence comes from a clinical trial completed by our research group. In a preliminary 12-week, double blind, placebo controlled trial of citalopram for cocaine dependence, citalopram produced a significant reduction in cocaine positive urines compared to placebo. Based on what is known regarding the role of the orbito-frontal cortex (OFC) and striatum in addiction and the effects of 5-HT manipulation on OFC function, there is evidence supporting the hypothesis that the reduction in cocaine use achieved by citalopram is related to change in striatal dopamine function mediated in part by changes in OFC serotonin. Combined with the positive preliminary findings from our previous clinical study with citalopram, this provides a strong rationale for further studies of citalopram as a treatment for cocaine dependence. This study builds upon compelling evidence supporting citalopram as a treatment medication for cocaine dependence, based on a conceptual model of prefrontal-striatal interactions. In the context of a randomized, double-blind, placebo-controlled, intent-to-treat, 3-arm, parallel design, single site study, with a sample size of N=125 cocaine dependent subjects, we expect to confirm the hypothesis that citalopram reduces cocaine use during treatment and increases abstinence rates at the end of treatment compared to placebo. Secondary analyses will test behavioral markers as predictors of treatment response based on the conceptual model of citalopram on fronto-striatal function.